Design, Synthesis and X‐Ray Structural Studies of Potent HIV‐1 Protease Inhibitors Containing C‐4 Substituted Tricyclic Hexahydro‐Furofuran Derivatives as P2 Ligands

Abstract

The design, synthesis, X-ray structural, and biological evaluation of a series of highly potent HIV-1 protease inhibitors are reported herein. These inhibitors incorporate novel cyclohexane-fused tricyclic bis-tetrahydrofuran as P2 ligands in combination with a variety of P1 and P2' ligands. The inhibitor with a difluoromethylphenyl P1 ligand and a cyclopropylaminobenzothiazole P2' ligand exhibited the most potent antiviral activity. Also, it maintained potent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The corresponding inhibitor with an enantiomeric ligand was significantly less potent in these antiviral assays. The new P2 ligands were synthesized in optically active form using enzymatic desymmetrization of meso-diols as the key step. To obtain molecular insight, two high-resolution X-ray structures of inhibitor-bound HIV-1 protease were determined and structural analyses have been highlighted.

Fluorinated Protein–Ligand Complexes: A Computational Perspective

“…Nevertheless, fluorine hydrogen bonds are frequently observed in protein–ligand complexes, particularly if the fluorinated ligand is a small organic molecule. Protein targets include FXIa, μ opioid receptor, YAP:TEAD protein–protein interaction, S1P receptor, Akt1, HIV protease, tyrosinase, Bruton’s tyrosine kinase, Janus kinases, and the SARS-CoV-2 main protease. − Thus, hydrogen bonds with fluorine as an acceptor are by no means a marginal phenomenon in protein–ligand systems. Whether they are a driving force for the stability of a protein–ligand complex and can thus be exploited as a design element is, however, questionable.…”